VEMLIDY 25mg film-coated tablets medication leaflet

Vemlidy 25 mg film-coated tablets.

Each film-coated tablet contains tenofovir alafenamide fumarate equivalent to 25 mg of tenofoviralafenamide.

Each tablet contains 95 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

Yellow, round, film-coated tablets, 8 mm in diameter, debossed with “GSI” on one side of the tabletand “25” on the other side of the tablet.

Vemlidy is indicated for the treatment of chronic hepatitis B (CHB) in adults and paediatric patients6 years of age and older weighing at least 25 kg (see section 5.1).

Therapy should be initiated by a physician experienced in the management of CHB.

Adults and paediatric patients at least 6 years of age and older weighing at least 25 kg: one tablet oncedaily.

Treatment discontinuation may be considered as follows (see section 4.4):

* In HBeAg-positive patients without cirrhosis, treatment should be administered for at least 6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection)is confirmed or until HBs seroconversion or until there is loss of efficacy (see section 4.4).

Regular reassessment is recommended after treatment discontinuation to detect virologicalrelapse.

* In HBeAg-negative patients without cirrhosis, treatment should be administered at least until

HBs seroconversion or until there is evidence of loss of efficacy. With prolonged treatment formore than 2 years, regular reassessment is recommended to confirm that continuing the selectedtherapy remains appropriate for the patient.

If a dose is missed and less than 18 hours have passed from the time it is usually taken, the patientshould take this medicinal product as soon as possible and then resume their normal dosing schedule.

If more than 18 hours have passed from the time it is usually taken, the patient should not take themissed dose and should simply resume the normal dosing schedule.

If the patient vomits within 1 hour of taking the treatment, the patient should take another tablet. If thepatient vomits more than 1 hour after taking the treatment, the patient does not need to take anothertablet.

No dose adjustment of this medicinal product is required in patients aged 65 years and older(see section 5.2).

No dose adjustment of this medicinal product is required in adults or adolescents (aged at least12 years and of at least 35 kg body weight) with estimated creatinine clearance (CrCl) ≥ 15 mL/min orin patients with CrCl < 15 mL/min who are receiving haemodialysis.

On days of haemodialysis, this medicinal product should be administered after completion ofhaemodialysis treatment (see section 5.2).

No dosing recommendations can be given for patients with CrCl < 15 mL/min who are not receivinghaemodialysis (see section 4.4).

No data are available to make dose recommendations in children aged less than 12 years and of lessthan 35 kg body weight with renal impairment.

No dose adjustment of this medicinal product is required in patients with hepatic impairment (seesections 4.4 and 5.2).

The safety and efficacy of Vemlidy in children younger than 6 years of age or weighing < 25 kg havenot yet been established. No data are available.

Oral use. Vemlidy film-coated tablets should be taken with food (see section 5.2).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hepatitis B Virus (HBV) transmission

Patients must be advised that this medicinal product does not prevent the risk of transmission of HBVto others through sexual contact or contamination with blood. Appropriate precautions must continueto be used.

Patients with decompensated liver disease

There are limited data on the safety and efficacy of tenofovir alafenamide in HBV infected patientswith decompensated liver disease and who have a Child Pugh Turcotte (CPT) score > 9 (i.e. class C).

These patients may be at higher risk of experiencing serious hepatic or renal adverse reactions.

Therefore, hepatobiliary and renal parameters should be closely monitored in this patient population(see section 5.2).

Exacerbation of hepatitis

Flares on treatment

Spontaneous exacerbations in CHB are relatively common and are characterised by transient increasesin serum alanine aminotransferase (ALT). After initiating antiviral therapy, serum ALT may increasein some patients. In patients with compensated liver disease, these increases in serum ALT aregenerally not accompanied by an increase in serum bilirubin concentrations or hepaticdecompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation followinghepatitis exacerbation, and therefore should be monitored closely during therapy.

Flares after treatment discontinuation

Acute exacerbation of hepatitis has been reported in patients who have discontinued treatment for

CHB, usually in association with rising HBV DNA levels in plasma. The majority of cases areself-limited but severe exacerbations, including fatal outcomes, may occur after discontinuation oftreatment for CHB. Hepatic function should be monitored at repeated intervals with both clinical andlaboratory follow-up for at least 6 months after discontinuation of treatment for CHB. If appropriate,resumption of CHB therapy may be warranted.

In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommendedsince post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Liver flares areespecially serious, and sometimes fatal in patients with decompensated liver disease.

Patients with creatinine clearance < 30 mL/min

The use of tenofovir alafenamide once daily in patients with CrCl ≥ 15 mL/min and < 30 mL/min isbased on Week 96 data on the efficacy and safety of switching from another antiviral regimen totenofovir alafenamide in an open-label clinical study of virologically suppressed HBV-infectedpatients (see sections 4.8 and 5.1). There are very limited data on the safety and efficacy of tenofoviralafenamide in HBV-infected patients with CrCl < 15 mL/min on chronic haemodialysis (seesections 4.8, 5.1 and 5.2).

The use of this medicinal product is not recommended in patients with CrCl < 15 mL/min who are notreceiving haemodialysis (see section 4.2).

Post-marketing cases of renal impairment, including acute renal failure and proximal renaltubulopathy have been reported with tenofovir alafenamide-containing products. A potential risk ofnephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofoviralafenamide cannot be excluded (see section 5.3).

It is recommended that renal function is assessed in all patients prior to, or when initiating, therapywith this treatment and that it is also monitored during therapy in all patients as clinically appropriate.

In patients who develop clinically significant decreases in renal function, or evidence of proximalrenal tubulopathy, discontinuation of this medicinal product should be considered.

Patients co-infected with HBV and hepatitis C or D virus

There are no data on the safety and efficacy of tenofovir alafenamide in patients co-infected withhepatitis C (HCV) or D (HDV) virus. Co-administration guidance for the treatment of HCV should befollowed (see section 4.5).

HBV and Human Immunodeficiency Virus (HIV) co-infection

HIV antibody testing should be offered to all HBV infected patients whose HIV-1 infection status isunknown before initiating therapy with this medicinal product. In patients who are co-infected with

HBV and HIV, Vemlidy should be co-administered with other antiretroviral medicinal products toensure that the patient receives an appropriate regimen for treatment of HIV (see section 4.5).

Co-administration with other medicinal products

This medicinal product should not be co-administered with medicinal products containing tenofoviralafenamide, tenofovir disoproxil or adefovir dipivoxil.

Co-administration of this treatment with certain anticonvulsants (e.g. carbamazepine, oxcarbazepine,phenobarbital and phenytoin), antimycobacterials (e.g. rifampicin, rifabutin and rifapentine) or

St. John’s wort, all of which are inducers of P-glycoprotein (P-gp) and may decrease tenofoviralafenamide plasma concentrations, is not recommended.

Co-administration of this treatment with strong inhibitors of P-gp (e.g. itraconazole and ketoconazole)may increase tenofovir alafenamide plasma concentrations. Co-administration is not recommended.

Reductions in bone mineral density (BMD ≥ 4%) of the lumbar spine and of whole body have beenreported in some paediatric patients 6 years of age and older weighing at least 25 kg who receivedtenofovir alafenamide for 48 weeks (see sections 4.8 and 5.1). The long-term effects of changes in

BMD on the growing bone, including the risk of fracture, are uncertain. A multidisciplinary approachis recommended to decide the appropriate monitoring during treatment.

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems ofgalactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take thismedicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Interaction studies have only been performed in adults.

This medicinal product should not be co-administered with medicinal products containing tenofovirdisoproxil, tenofovir alafenamide or adefovir dipivoxil.

Medicinal products that may affect tenofovir alafenamide

Tenofovir alafenamide is transported by P-gp and breast cancer resistance protein (BCRP). Medicinalproducts that are P-gp inducers (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital or

St. John’s wort) are expected to decrease plasma concentrations of tenofovir alafenamide, which maylead to loss of therapeutic effect of Vemlidy. Co-administration of such medicinal products withtenofovir alafenamide is not recommended.

Co-administration of tenofovir alafenamide with medicinal products that inhibit P-gp and BCRP mayincrease plasma concentrations of tenofovir alafenamide. Co-administration of strong inhibitors of

P-gp with tenofovir alafenamide is not recommended.

Tenofovir alafenamide is a substrate of OATP1B1 and OATP1B3 in vitro. The distribution oftenofovir alafenamide in the body may be affected by the activity of OATP1B1 and/or OATP1B3.

Effect of tenofovir alafenamide on other medicinal products

Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or

CYP2D6 in vitro. It is not an inhibitor or inducer of CYP3A in vivo.

Tenofovir alafenamide is not an inhibitor of human uridine diphosphate glucuronosyltransferase(UGT) 1A1 in vitro. It is not known whether tenofovir alafenamide is an inhibitor of other

UGT enzymes.

Drug interaction information for Vemlidy with potential concomitant medicinal products issummarised in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”; twicedaily as “b.i.d.”, single dose as “s.d.”, once daily as “q.d.”). The drug interactions described are basedon studies conducted with tenofovir alafenamide, or are potential drug interactions that may occurwith Vemlidy.

Table 1: Interactions Between Vemlidy and Other Medicinal Products

Medicinal product by Effects on drug levels.a,b Recommendation concerning co-administrationtherapeutic areas Mean ratio (90% with Vemlidyconfidence interval) for

AUC, Cmax, Cmin

ANTICONVULSANTS

Carbamazepine Tenofovir alafenamide Co-administration is not recommended.(300 mg orally, b.i.d.) ↓ Cmax 0.43 (0.36, 0.51)↓ AUC 0.45 (0.40, 0.51)

Tenofovir alafenamidec(25 mg orally, s.d.) Tenofovir↓ Cmax 0.70 (0.65, 0.74)↔ AUC 0.77 (0.74, 0.81)

Oxcarbazepine Interaction not studied. Co-administration is not recommended.

Phenobarbital Expected:↓ Tenofovir alafenamide

Phenytoin Interaction not studied. Co-administration is not recommended.

Expected:↓ Tenofovir alafenamide

Midazolamd Midazolam No dose adjustment of midazolam (administered(2.5 mg orally, s.d.) ↔ Cmax 1.02 (0.92, 1.13) orally or intravenously) is required.↔ AUC 1.13 (1.04, 1.23)

Tenofovir alafenamidec(25 mg orally, q.d.)

Midazolamd Midazolam(1 mg intravenously, s.d.) ↔ Cmax 0.99 (0.89, 1.11)↔ AUC 1.08 (1.04, 1.14)

Tenofovir alafenamidec(25 mg orally, q.d.)

Medicinal product by Effects on drug levels.a,b Recommendation concerning co-administrationtherapeutic areas Mean ratio (90% with Vemlidyconfidence interval) for

AUC, Cmax, Cmin

ANTIDEPRESSANTS

Sertraline Tenofovir alafenamide No dose adjustment of Vemlidy or sertraline is(50 mg orally, s.d.) ↔ Cmax 1.00 (0.86, 1.16) required.↔ AUC 0.96 (0.89, 1.03)

Tenofovir alafenamidee(10 mg orally, q.d.) Tenofovir↔ Cmax 1.10 (1.00, 1.21)↔ AUC 1.02 (1.00, 1.04)↔ Cmin 1.01 (0.99, 1.03)

Sertraline Sertraline(50 mg orally, s.d.) ↔ Cmax 1.14 (0.94, 1.38)↔ AUC 0.93 (0.77, 1.13)

Tenofovir alafenamidee(10 mg orally, q.d.)

ANTIFUNGALS

Itraconazole Interaction not studied. Co-administration is not recommended.

Ketoconazole Expected:

↑ Tenofovir alafenamide

ANTIMYCOBACTERIALS

Rifampicin Interaction not studied. Co-administration is not recommended.

Rifapentine Expected:

↓ Tenofovir alafenamide

Rifabutin Interaction not studied. Co-administration is not recommended.

Expected:↓ Tenofovir alafenamide

HCV ANTIVIRAL AGENTS

Sofosbuvir (400 mg orally, Interaction not studied. No dose adjustment of Vemlidy or sofosbuvir isq.d.) Expected: required.

↔ Sofosbuvir↔ GS-331007

Ledipasvir/sofosbuvir Ledipasvir No dose adjustment of Vemlidy or(90 mg/400 mg orally, q.d.) ↔ Cmax 1.01 (0.97, 1.05) ledipasvir/sofosbuvir is required.↔ AUC 1.02 (0.97, 1.06)

Tenofovir alafenamidef ↔ Cmin 1.02 (0.98, 1.07)(25 mg orally, q.d.)

Sofosbuvir↔ Cmax 0.96 (0.89, 1.04)↔ AUC 1.05 (1.01, 1.09)

GS-331007g↔ Cmax 1.08 (1.05, 1.11)↔ AUC 1.08 (1.06, 1.10)↔ Cmin 1.10 (1.07, 1.12)

Tenofovir alafenamide↔ Cmax 1.03 (0.94, 1.14)↔ AUC 1.32 (1.25, 1.40)

Tenofovir↑ Cmax 1.62 (1.56, 1.68)↑ AUC 1.75 (1.69, 1.81)↑ Cmin 1.85 (1.78, 1.92)

Sofosbuvir/velpatasvir Interaction not studied. No dose adjustment of Vemlidy or(400 mg/100 mg orally, Expected: sofosbuvir/velpatasvir is required.q.d.) ↔ Sofosbuvir↔ GS-331007↔ Velpatasvir↑ Tenofovir alafenamide

Medicinal product by Effects on drug levels.a,b Recommendation concerning co-administrationtherapeutic areas Mean ratio (90% with Vemlidyconfidence interval) for

AUC, Cmax, Cmin

Sofosbuvir/velpatasvir/ Sofosbuvir No dose adjustment of Vemlidy orvoxilaprevir ↔ Cmax 0.95 (0.86, 1.05) sofosbuvir/velpatasvir/voxilaprevir is required.(400 mg/100 mg/ ↔ AUC 1.01 (0.97, 1.06)100 mg + 100 mgi orally,q.d.) GS-331007g↔ Cmax 1.02 (0.98, 1.06)

Tenofovir alafenamidef ↔ AUC 1.04 (1.01, 1.06)(25 mg orally, q.d.)

Velpatasvir↔ Cmax 1.05 (0.96, 1.16)↔ AUC 1.01 (0.94, 1.07)↔ Cmin 1.01 (0.95, 1.09)

Voxilaprevir↔ Cmax 0.96 (0.84, 1.11)↔ AUC 0.94 (0.84, 1.05)↔ Cmin 1.02 (0.92, 1.12)

Tenofovir alafenamide↑ Cmax 1.32 (1.17, 1.48)↑ AUC 1.52 (1.43, 1.61)

HIV ANTIRETROVIRAL AGENTS - PROTEASE INHIBITORS

Atazanavir/cobicistat Tenofovir alafenamide Co-administration is not recommended.(300 mg/150 mg orally, ↑ Cmax 1.80 (1.48, 2.18)q.d.) ↑ AUC 1.75 (1.55, 1.98)

Tenofovir alafenamidec Tenofovir(10 mg orally, q.d.) ↑ Cmax 3.16 (3.00, 3.33)↑ AUC 3.47 (3.29, 3.67)↑ Cmin 3.73 (3.54, 3.93)

Atazanavir↔ Cmax 0.98 (0.94, 1.02)↔ AUC 1.06 (1.01, 1.11)↔ Cmin 1.18 (1.06, 1.31)

Cobicistat↔ Cmax 0.96 (0.92, 1.00)↔ AUC 1.05 (1.00, 1.09)↑ Cmin 1.35 (1.21, 1.51)

Atazanavir/ritonavir Tenofovir alafenamide Co-administration is not recommended.(300 mg/100 mg orally, ↑ Cmax 1.77 (1.28, 2.44)q.d.) ↑ AUC 1.91 (1.55, 2.35)

Tenofovir alafenamidec Tenofovir(10 mg orally, s.d.) ↑ Cmax 2.12 (1.86, 2.43)↑ AUC 2.62 (2.14, 3.20)

Atazanavir↔ Cmax 0.98 (0.89, 1.07)↔ AUC 0.99 (0.96, 1.01)↔ Cmin 1.00 (0.96, 1.04)

Medicinal product by Effects on drug levels.a,b Recommendation concerning co-administrationtherapeutic areas Mean ratio (90% with Vemlidyconfidence interval) for

AUC, Cmax, Cmin

Darunavir/cobicistat Tenofovir alafenamide Co-administration is not recommended.(800 mg/150 mg orally, ↔ Cmax 0.93 (0.72, 1.21)q.d.) ↔ AUC 0.98 (0.80, 1.19)

Tenofovir alafenamidec Tenofovir(25 mg orally, q.d.) ↑ Cmax 3.16 (3.00, 3.33)↑ AUC 3.24 (3.02, 3.47)↑ Cmin 3.21 (2.90, 3.54)

Darunavir↔ Cmax 1.02 (0.96, 1.09)↔ AUC 0.99 (0.92, 1.07)↔ Cmin 0.97 (0.82, 1.15)

Cobicistat↔ Cmax 1.06 (1.00, 1.12)↔ AUC 1.09 (1.03, 1.15)↔ Cmin 1.11 (0.98, 1.25)

Darunavir/ritonavir Tenofovir alafenamide Co-administration is not recommended.(800 mg/100 mg orally, ↑ Cmax 1.42 (0.96, 2.09)q.d.) ↔ AUC 1.06 (0.84, 1.35)

Tenofovir alafenamidec Tenofovir(10 mg orally, s.d.) ↑ Cmax 2.42 (1.98, 2.95)↑ AUC 2.05 (1.54, 2.72)

Darunavir↔ Cmax 0.99 (0.91, 1.08)↔ AUC 1.01 (0.96, 1.06)↔ Cmin 1.13 (0.95, 1.34)

Lopinavir/ritonavir Tenofovir alafenamide Co-administration is not recommended.(800 mg/200 mg orally, ↑ Cmax 2.19 (1.72, 2.79)q.d.) ↑ AUC 1.47 (1.17, 1.85)

Tenofovir alafenamidec Tenofovir(10 mg orally, s.d.) ↑ Cmax 3.75 (3.19, pct. 4.39)↑ AUC 4.16 (3.50, 4.96)

Lopinavir↔ Cmax 1.00 (0.95, 1.06)↔ AUC 1.00 (0.92, 1.09)↔ Cmin 0.98 (0.85, 1.12)

Tipranavir/ritonavir Interaction not studied. Co-administration is not recommended.

Expected:↓ Tenofovir alafenamide

HIV ANTIRETROVIRAL AGENTS - INTEGRASE INHIBITORS

Dolutegravir Tenofovir alafenamide No dose adjustment of Vemlidy or dolutegravir is(50 mg orally, q.d.) ↑ Cmax 1.24 (0.88, 1.74) required.↑ AUC 1.19 (0.96, 1.48)

Tenofovir alafenamidec(10 mg orally, s.d.) Tenofovir↔ Cmax 1.10 (0.96, 1.25)↑ AUC 1.25 (1.06, 1.47)

Dolutegravir↔ Cmax 1.15 (1.04, 1.27)↔ AUC 1.02 (0.97, 1.08)↔ Cmin 1.05 (0.97, 1.13)

Medicinal product by Effects on drug levels.a,b Recommendation concerning co-administrationtherapeutic areas Mean ratio (90% with Vemlidyconfidence interval) for

AUC, Cmax, Cmin

Raltegravir Interaction not studied. No dose adjustment of Vemlidy or raltegravir is

Expected: required.↔ Tenofovir alafenamide↔ Raltegravir

HIV ANTIRETROVIRAL AGENTS - NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Efavirenz Tenofovir alafenamide No dose adjustment of Vemlidy or efavirenz is(600 mg orally, q.d.) ↓ Cmax 0.78 (0.58, 1.05) required.↔ AUC 0.86 (0.72, 1.02)

Tenofovir alafenamideh(40 mg orally, q.d.) Tenofovir↓ Cmax 0.75 (0.67, 0.86)↔ AUC 0.80 (0.73, 0.87)↔ Cmin 0.82 (0.75, 0.89)

Expected:↔ Efavirenz

Nevirapine Interaction not studied. No dose adjustment of Vemlidy or nevirapine is

Expected: required.↔ Tenofovir alafenamide↔ Nevirapine

Rilpivirine Tenofovir alafenamide No dose adjustment of Vemlidy or rilpivirine is(25 mg orally, q.d.) ↔ Cmax 1.01 (0.84, 1.22) required.↔ AUC 1.01 (0.94, 1.09)

Tenofovir alafenamide(25 mg orally, q.d.) Tenofovir↔ Cmax 1.13 (1.02, 1.23)↔ AUC 1.11 (1.07, 1.14)↔ Cmin 1.18 (1.13, 1.23)

Rilpivirine↔ Cmax 0.93 (0.87, 0.99)↔ AUC 1.01 (0.96, 1.06)↔ Cmin 1.13 (1.04, 1.23)

HIV ANTIRETROVIRAL AGENTS - CCR5 RECEPTOR ANTAGONIST

Maraviroc Interaction not studied. No dose adjustment of Vemlidy or maraviroc is

Expected: required.↔ Tenofovir alafenamide↔ Maraviroc

HERBAL SUPPLEMENTS

St. John’s wort (Hypericum Interaction not studied. Co-administration is not recommended.perforatum) Expected:

↓ Tenofovir alafenamide

ORAL CONTRACEPTIVES

Norgestimate Norelgestromin No dose adjustment of Vemlidy or(0.180 mg/0.215 mg/ ↔ Cmax 1.17 (1.07, 1.26) norgestimate/ethinyl estradiol is required.0.250 mg orally, q.d.) ↔ AUC 1.12 (1.07, 1.17)↔ Cmin 1.16 (1.08, 1.24)

Ethinylestradiol(0.025 mg orally, q.d.) Norgestrel↔ Cmax 1.10 (1.02, 1.18)

Tenofovir alafenamidec ↔ AUC 1.09 (1.01, 1.18)(25 mg orally, q.d.) ↔ Cmin 1.11 (1.03, 1.20)

Ethinylestradiol↔ Cmax 1.22 (1.15, 1.29)↔ AUC 1.11 (1.07, 1.16)↔ Cmin 1.02 (0.93, 1.12)a All interaction studies are conducted in healthy volunteers.

b All No Effect Boundaries are 70%-143%.c Study conducted with emtricitabine/tenofovir alafenamide fixed-dose combination tablet.d A sensitive CYP3A4 substrate.e Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fixed-dose combination tablet.f Study conducted with emtricitabine/rilpivirine/tenofovir alafenamide fixed-dose combination tablet.g The predominant circulating nucleoside metabolite of sofosbuvir.h Study conducted with tenofovir alafenamide 40 mg and emtricitabine 200 mg.i Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV infectedpatients.

A moderate amount of data on pregnant women exposed to tenofovir alafenamide (between 300-1000pregnancy outcomes) indicate no malformative or feto/neonatal toxicity.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity(see section 5.3).

The use of tenofovir alafenamide may be considered during pregnancy, if necessary.

Based on published data, tenofovir alafenamide and tenofovir are excreted in human milk at low levelsin women administered with tenofovir alafenamide. There is insufficient information on the effects oftenofovir in newborns/infants.

A risk to the breast-fed newborns/infants cannot be excluded; therefore, tenofovir alafenamide shouldnot be used during breast-feeding.

No human data on the effect of tenofovir alafenamide on fertility are available. Animal studies do notindicate harmful effects of tenofovir alafenamide on fertility.

Vemlidy may have minor influence on the ability to drive and use machines. Patients should beinformed that dizziness has been reported during treatment with tenofovir alafenamide.

Assessment of adverse reactions is based on clinical study data and postmarketing data. In pooledsafety data from 2 controlled Phase 3 studies (GS-US-320-0108 and GS-US-320-0110; “Study 108”and “Study 110”, respectively), the most frequently reported adverse reactions at Week 96 analysiswere headache (12%), nausea (6%), and fatigue (6%). After Week 96, patients either remained on theiroriginal blinded treatment up to Week 144 or received open-label tenofovir alafenamide.

The safety profile of tenofovir alafenamide was similar in virologically suppressed patients switchingfrom tenofovir disoproxil to tenofovir alafenamide in Study 108, Study 110 and a controlled Phase 3study GS-US-320-4018 (“Study 4018”). Changes in lipid laboratory tests were observed in thesestudies following a switch from tenofovir disoproxil (see section 5.1).

The following adverse reactions have been identified with tenofovir alafenamide in patients with CHB(Table 2). The adverse reactions are listed below by body system organ class and frequency based onthe Week 96 analysis. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to< 1/10) or uncommon (≥ 1/1,000 to < 1/100).

Table 2: Adverse Reactions Identified with Tenofovir Alafenamide

System organ class

Frequency Adverse reaction

Very common Headache

Common Dizziness

Common Diarrhoea, vomiting, nausea, abdominal pain, abdominal distension, flatulence

Common Increased ALT

Common Rash, pruritus

Uncommon Angioedema1, urticaria1

Common Arthralgia

Common Fatigue1 Adverse reaction identified through post-marketing surveillance for tenofovir alafenamide-containing products.

In the open-label Phase 2 study (GS-US-320-4035; “Study 4035”) to evaluate the efficacy and safetyof switching from another antiviral regimen to tenofovir alafenamide in virologically suppressed HBVinfected patients, small median increases in fasting total cholesterol, direct low density lipoprotein(LDL), high density lipoprotein (HDL), and triglycerides from baseline to Week 96 were observed inpatients with moderate or severe renal impairment (Part A Cohort 1) and patients with moderate orsevere hepatic impairment (Part B), consistent with changes observed in Studies 108 and 110. Smallmedian decreases in total cholesterol, LDL and triglycerides were observed in patients with ESRD onhemodialysis in Part A Cohort 2, while small median increases were observed in HDL from baselineto Week 96. Median (Q1, Q3) change from baseline at Week 96 in total cholesterol to HDL ratio was0.1 (-0.4, 0.4) in the moderate or severe renal impairment group, and -0.4 (-0.8,-0.1) in patients with

ESRD on hemodialysis and 0.1 (-0.2, 0.4) in patients with moderate or severe hepatic impairment.

Body weight and levels of blood lipids and glucose may increase during therapy.

In Study 4035 in virologically suppressed patients with moderate to severe renal impairment (eGFR by

Cockcroft-Gault method 15 to 59 mL/min; Part A, Cohort 1, N = 78), end stage renal disease (ESRD)(eGFR < 15 mL/min) on haemodialysis (Part A, Cohort 2, N = 15), and/or moderate to severe hepaticimpairment (Child-Pugh Class B or C at screening or by history; Part B, N = 31) who switched fromanother antiviral regimen to tenofovir alafenamide, no additional adverse reactions to tenofoviralafenamide were identified through Week 96.

The safety of tenofovir alafenamide was evaluated in 88 HBV-infected treatment-naïve and treatment-experienced paediatric patients between the ages of 12 to < 18 years weighing ≥ 35 kg (tenofoviralafenamide group N=47, placebo group N=23) and 6 to < 12 years weighing ≥ 25 kg (tenofoviralafenamide group N=12, placebo group N=6) through Week 24 in a randomised, double-blind,placebo-controlled clinical study GS-US-320-1092 (“Study 1092”). After the double-blind phase,patients were switched to open-label tenofovir alafenamide at Week 24. The safety profile of tenofoviralafenamide in paediatric patients was comparable to that in adults. Reductions in bone mineraldensity (BMD ≥ 4%) of the lumbar spine and of whole body have been reported in some paediatricpatients 6 years of age and older weighing at least 25 kg who received tenofovir alafenamide for up to48 weeks (see sections 4.4 and 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8).

Treatment of overdose with tenofovir alafenamide consists of general supportive measures includingmonitoring of vital signs as well as observation of the clinical status of the patient.

Tenofovir is efficiently removed by haemodialysis with an extraction coefficient ofapproximately 54%. It is not known whether tenofovir can be removed by peritoneal dialysis.

Pharmacotherapeutic group: Antiviral for systemic use, nucleoside and nucleotide reversetranscriptase inhibitors; ATC code: J05AF13.

Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (2’-deoxyadenosinemonophosphate analogue). Tenofovir alafenamide enters primary hepatocytes by passive diffusion andby the hepatic uptake transporters OATP1B1 and OATP1B3. Tenofovir alafenamide is primarilyhydrolysed to form tenofovir by carboxylesterase 1 in primary hepatocytes. Intracellular tenofovir issubsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate.

Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the

HBV reverse transcriptase, which results in DNA chain termination.

Tenofovir has activity that is specific to HBV and HIV (HIV-1 and HIV-2). Tenofovir diphosphate isa weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ andthere is no evidence of mitochondrial toxicity in vitro based on several assays including mitochondrial

DNA analyses.

The antiviral activity of tenofovir alafenamide was assessed in HepG2 cells against a panel of

HBV clinical isolates representing genotypes A-H. The EC50 (50% effective concentration) values fortenofovir alafenamide ranged from 34.7 to 134.4 nM, with an overall mean EC50 of 86.6 nM. The CC50(50% cytotoxicity concentration) in HepG2 cells was > 44,400 nM.

In patients receiving tenofovir alafenamide, sequence analysis was performed on paired baseline andon-treatment HBV isolates for patients who either experienced virologic breakthrough (2 consecutivevisits with HBV DNA ≥ 69 IU/mL after having been < 69 IU/mL, or 1.0 log10 or greater increase in

HBV DNA from nadir) or patients with HBV DNA ≥ 69 IU/mL at Week 48, or Week 96 or at earlydiscontinuation at or after Week 24.

In a pooled analysis of patients receiving tenofovir alafenamide in Study 108 and Study 110 at

Week 48 (N = 20) and Week 96 (N = 72), no amino acid substitutions associated with resistance totenofovir alafenamide were identified in these isolates (genotypic and phenotypic analyses).

In virologically suppressed patients receiving tenofovir alafenamide following switch from tenofovirdisoproxil treatment in Study 4018, through 96 weeks of tenofovir alafenamide treatment one patientin the tenofovir alafenamide-tenofovir alafenamide group experienced a virologic blip (one visit with

HBV DNA ≥ 69 IU/mL) and one patient in the tenofovir disoproxil-tenofovir alafenamide groupexperienced a virologic breakthrough. No HBV amino acid substitutions associated with resistance totenofovir alafenamide or tenofovir disoproxil were detected through 96 weeks of treatment.

In paediatric Study 1092, 30 patients aged 12 to < 18 years and 9 patients aged 6 to < 12 yearsreceiving tenofovir alafenamide qualified for resistance analysis at Week 24. No HBV amino acidsubstitutions associated with resistance to tenofovir alafenamide were detected through 24 weeks oftreatment. At Week 48, 31 patients aged 12 to < 18 years and 12 patients aged 6 to < 12 yearsqualified for resistance analysis (both tenofovir alafenamide group and placebo roll over to tenofoviralafenamide group at Week 24). No HBV amino acid substitutions associated with resistance totenofovir alafenamide were detected through 48 weeks of treatment.

The antiviral activity of tenofovir alafenamide was evaluated against a panel of isolates containingnucleos(t)ide reverse transcriptase inhibitor mutations in HepG2 cells. HBV isolates expressing thertV173L, rtL180M, and rtM204V/I substitutions associated with resistance to lamivudine remainedsusceptible to tenofovir alafenamide (< 2-fold change in EC50). HBV isolates expressing the rtL180M,rtM204V plus rtT184G, rtS202G, or rtM250V substitutions associated with resistance to entecavirremained susceptible to tenofovir alafenamide. HBV isolates expressing the rtA181T, rtA181V, orrtN236T single substitutions associated with resistance to adefovir remained susceptible to tenofoviralafenamide; however, the HBV isolate expressing rtA181V plus rtN236T exhibited reducedsusceptibility to tenofovir alafenamide (3.7-fold change in EC50). The clinical relevance of thesesubstitutions is not known.

The efficacy and safety of tenofovir alafenamide in patients with CHB are based on 48- and 96-weekdata from two randomised, double-blind, active-controlled studies, Study 108 and Study 110. Thesafety of tenofovir alafenamide is also supported by pooled data from patients in Studies 108 and 110who remained on blinded treatment from Week 96 through Week 144 and additionally from patientsin the open-label phase of Studies 108 and 110 from Week 96 through Week 144 (N = 360 remainedon tenofovir alafenamide; N = 180 switched from tenofovir disoproxil to tenofovir alafenamide at

Week 96).

In Study 108, HBeAg-negative treatment-naïve and treatment-experienced patients with compensatedliver function were randomised in a 2:1 ratio to receive tenofovir alafenamide (25 mg; N = 285) oncedaily or tenofovir disoproxil (245 mg; N = 140) once daily. The mean age was 46 years, 61% weremale, 72% were Asian, 25% were White and 2% (8 patients) were Black. 24%, 38%, and 31% had

HBV genotype B, C, and D, respectively. 21% were treatment-experienced (previous treatment withoral antivirals, including entecavir (N = 41), lamivudine (N = 42), tenofovir disoproxil (N = 21), orother (N = 18)). At baseline, mean plasma HBV DNA was 5.8 log10 IU/mL, mean serum ALT was94 U/L, and 9% of patients had a history of cirrhosis.

In Study 110, HBeAg-positive treatment-naïve and treatment-experienced patients with compensatedliver function were randomised in a 2:1 ratio to receive tenofovir alafenamide (25 mg; N = 581) oncedaily or tenofovir disoproxil (245 mg; N = 292) once daily. The mean age was 38 years, 64% weremale, 82% were Asian, 17% were White and < 1% (5 patients) were Black. 17%, 52%, and 23% had

HBV genotype B, C, and D, respectively. 26% were treatment-experienced (previous treatment withoral antivirals, including adefovir (N = 42), entecavir (N = 117), lamivudine (N = 84), telbivudine(N = 25), tenofovir disoproxil (N = 70), or other (N = 17)). At baseline, mean plasma HBV DNA was7.6 log10 IU/mL, mean serum ALT was 120 U/L, and 7% of patients had a history of cirrhosis.

The primary efficacy endpoint in both studies was the proportion of patients with plasma HBV DNAlevels below 29 IU/mL at Week 48. Tenofovir alafenamide met the non-inferiority criteria inachieving HBV DNA less than 29 IU/mL when compared to tenofovir disoproxil. Treatment outcomesof Study 108 and Study 110 through Week 48 are presented in Table 3 and Table 4.

Table 3: HBV DNA Efficacy Parameters at Week 48a

Study 108 (HBeAg-Negative) Study 110 (HBeAg-Positive)

TAF TDF TAF TDF(N = 285) (N = 140) (N = 581) (N = 292)

HBV DNA < 29 IU/mL 94% 93% 64% 67%

Treatment differenceb 1.8% (95% CI = -3.6% to 7.2%) -3.6% (95% CI = -9.8% to 2.6%)

HBV DNA ≥ 29 IU/mL 2% 3% 31% 30%

Baseline HBV DNA< 7 log10 IU/mL 96% (221/230) 92% (107/116) N/A N/A≥ 7 log10 IU/mL 85% (47/55) 96% (23/24)

Baseline HBV DNA< 8 log10 IU/mL N/A N/A 82% (254/309) 82% (123/150)≥ 8 log10 IU/mL 43% (117/272) 51% (72/142)

Nucleoside naïvec 94% (212/225) 93% (102/110) 68% (302/444) 70% (156/223)

Nucleoside experienced 93% (56/60) 93% (28/30) 50% (69/137) 57% (39/69)

No Virologic dataat Week 48 4% 4% 5% 3%

Discontinued study drugdue to lack of efficacy 0 0 < 1% 0

Discontinued study drugdue to AE or death 1% 1% 1% 1%

Discontinued study drugdue to other reasonsd 2% 3% 3% 2%

Missing data duringwindow but on study drug < 1% 1% < 1% 0

N/A = not applicable

TDF = tenofovir disoproxil

TAF = tenofovir alafenamidea Missing = failure analysis.b Adjusted by baseline plasma HBV DNA categories and oral antiviral treatment status strata.c Treatment-naïve patients received < 12 weeks of oral antiviral treatment with any nucleoside or nucleotide analogueincluding tenofovir disoproxil or tenofovir alafenamide.d Includes patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy, e.g.

withdrew consent, loss to follow-up, etc.

Table 4: Additional Efficacy Parameters at Week 48a

Study 108 (HBeAg-Negative) Study 110 (HBeAg-Positive)

TAF TDF TAF TDF(N = 285) (N = 140) (N = 581) (N = 292)

ALT

Normalised ALT (Central lab)b 83% 75% 72% 67%

Normalised ALT (AASLD)c 50% 32% 45% 36%

Serology

HBeAg loss/seroconversiond N/A N/A 14%/10% 12%/8%

HBsAg loss/seroconversion 0/0 0/0 1%/1% < 1%/0

N/A = not applicable

TDF = tenofovir disoproxil

TAF = tenofovir alafenamidea Missing = failure analysis.b The population used for analysis of ALT normalisation included only patients with ALT above upper limit ofnormal (ULN) of the central laboratory range at baseline. Central laboratory ULN for ALT are as follows: ≤ 43 U/L formales aged 18 to < 69 years and ≤ 35 U/L for males ≥ 69 years; ≤ 34 U/L for females 18 to < 69 years and ≤ 32 U/L forfemales ≥ 69 years.

c The population used for analysis of ALT normalisation included only patients with ALT above ULN of the 2016

American Association of the Study of Liver Diseases (AASLD) criteria (> 30 U/L males and > 19 U/L females) atbaseline.

d The population used for serology analysis included only patients with antigen (HBeAg) positive and antibody (HBeAb)negative or missing at baseline.

Experience beyond 48 weeks in Study 108 and Study 110

At Week 96, viral suppression as well as biochemical and serological responses were maintained withcontinued tenofovir alafenamide treatment (see Table 5).

Table 5: HBV DNA and Additional Efficacy Parameters at Week 96a

Study 108 (HBeAg-Negative) Study 110 (HBeAg-Positive)

TAF TDF TAF TDF(N = 285) (N = 140) (N = 581) (N = 292)

HBV DNA < 29 IU/mL 90% 91% 73% 75%

Baseline HBV DNA< 7 log10 IU/mL 90% (207/230) 91% (105/116) N/A N/A≥ 7 log10 IU/mL 91% (50/55) 92% (22/24)

Baseline HBV DNA< 8 log10 IU/mL N/A N/A 84% (260/309) 81% (121/150)≥ 8 log10 IU/mL 60% (163/272) 68% (97/142)

Nucleoside-naïveb 90% (203/225) 92% (101/110) 75% (331/444) 75% (168/223)

Nucleoside-experienced 90% (54/60) 87% (26/30) 67% (92/137) 72% (50/69)

ALT

Normalised ALT (Central lab)c 81% 71% 75% 68%

Normalised ALT (AASLD)d 50% 40% 52% 42%

Serology

HBeAg loss/seroconversione N/A N/A 22%/18% 18%/12%

HBsAg loss/seroconversion < 1%/< 1% 0/0 1%/1% 1%/0

N/A = not applicable

TDF = tenofovir disoproxil

TAF = tenofovir alafenamidea Missing = failure analysisb Treatment-naïve patients received < 12 weeks of oral antiviral treatment with any nucleoside or nucleotide analogueincluding tenofovir disoproxil or tenofovir alafenamide.c The population used for analysis of ALT normalisation included only patients with ALT above ULN of the centrallaboratory range at baseline. Central laboratory ULN for ALT are as follows: ≤ 43 U/L for males aged 18 to < 69 yearsand ≤ 35 U/L for males ≥ 69 years; ≤ 34 U/L for females 18 to < 69 years and ≤ 32 U/L for females ≥ 69 years.

d The population used for analysis of ALT normalisation included only patients with ALT above ULN of the 2016 AASLDcriteria (> 30 U/L males and > 19 U/L females) at baseline.

e The population used for serology analysis included only patients with antigen (HBeAg) positive and antibody (HBeAb)negative or missing at baseline.

Changes in measures of bone mineral density in Study 108 and Study 110

In both studies tenofovir alafenamide was associated with smaller mean percentage decreases in BMD(as measured by hip and lumbar spine dual energy X ray absorptiometry [DXA] analysis) compared totenofovir disoproxil after 96 weeks of treatment.

In patients who remained on blinded treatment beyond Week 96, mean percentage change in BMD ineach group at Week 144 was similar to that at Week 96. In the open-label phase of both studies, meanpercentage change in BMD from Week 96 to Week 144 in patients who remained on tenofoviralafenamide was +0.4% at the lumbar spine and -0.3% at the total hip, compared to +2.0% at thelumbar spine and +0.9% at the total hip in those who switched from tenofovir disoproxil to tenofoviralafenamide at Week 96.

Changes in measures of renal function in Study 108 and Study 110

In both studies tenofovir alafenamide was associated with smaller changes in renal safety parameters(smaller median reductions in estimated CrCl by Cockcroft-Gault and smaller median percentageincreases in urine retinol binding protein to creatinine ratio and urine beta-2-microglobulin tocreatinine ratio) compared to tenofovir disoproxil after 96 weeks of treatment (see also section 4.4).

In patients who remained on blinded treatment beyond Week 96 in Studies 108 and 110, changes frombaseline in renal laboratory parameter values in each group at Week 144 were similar to those at

Week 96. In the open-label phase of Studies 108 and 110, the mean (SD) change in serum creatininefrom Week 96 to Week 144 was +0.002 (0.0924) mg/dL in those who remained on tenofoviralafenamide, compared to -0.018 (0.0691) mg/dL in those who switched from tenofovir disoproxil totenofovir alafenamide at Week 96. In the open-label phase, the median change in eGFR from Week 96to Week 144 was -1.2 mL/min in patients who remained on tenofovir alafenamide, compared to+4.2 mL/min in patients who switched from tenofovir disoproxil to tenofovir alafenamide at Week 96.

Changes in lipid laboratory tests in Study 108 and Study 110

In a pooled analysis of Studies 108 and 110, median changes in fasting lipid parameters from baselineto Week 96 were observed in both treatment groups. For patients who switched to open label tenofoviralafenamide at Week 96, changes from double-blind baseline for patients randomised initially totenofovir alafenamide and tenofovir disoproxil at Week 96 and Week 144 in total cholesterol,

HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio are presented in

Table 6. At Week 96, the end of the double-blind phase, decreases in median fasting total cholesteroland HDL, and increases in median fasting direct LDL and triglycerides were observed in the tenofoviralafenamide group, while the tenofovir disoproxil group demonstrated median reductions in allparameters.

In the open-label phase of Studies 108 and 110, where patients switched to open-label tenofoviralafenamide at Week 96, lipid parameters at Week 144 in patients who remained on tenofoviralafenamide were similar to those at Week 96, whereas median increases in fasting total cholesterol,direct LDL, HDL, and triglycerides were observed in patients who switched from tenofovir disoproxilto tenofovir alafenamide at Week 96. In the open label phase, median (Q1, Q3) change from Week 96to Week 144 in total cholesterol to HDL ratio was 0.0 (-0.2, 0.4) in patients who remained ontenofovir alafenamide and 0.2 (-0.2, 0.6) in patients who switched from tenofovir disoproxil totenofovir alafenamide at Week 96.

Table 6: Median Changes from Double-Blind Baseline in Lipid Laboratory Tests at

Weeks 96 and 144 for Patients Who Switched to Open-Label Tenofovir Alafenamide at Week 96

TAF-TAF(N=360)

Double blind Week 96 Week 144baseline

Median (Q1, Q3) Median change (Q1, Q3) Median change (Q1, Q3)(mg/dL) (mg/dL) (mg/dL)

Total Cholesterol (fasted) 185 (166, 210) 0 (-18, 17) 0 (-16, 18)

HDL-Cholesterol (fasted) 59 (49, 72) -5 (-12, 1)a -5 (-12,2)b

LDL-Cholesterol (fasted) 113 (95, 137) 6 (-8, 21)a 8 (-6, 24)b

Triglycerides (fasted) 87 (67, 122) 8 (-12, 28)a 11 (-11, 40)b

Total Cholesterol to HDL ratio 3.1 (2.6, 3.9) 0.2 (0.0, 0.6)a 0.3 (0.0, 0.7)b

TDF-TAF(N=180)

Double blind Week 96 Week 144baseline

Median (Q1, Q3) Median change (Q1, Q3) Median change (Q1, Q3)(mg/dL) (mg/dL) (mg/dL)

Total Cholesterol (fasted) 189 (163, 215) -23 (-40, -1)a 1 (-17, 20)

HDL-Cholesterol (fasted) 61 (49, 72) -12 (-19, -3)a -8 (-15, -1)b

LDL-Cholesterol (fasted) 120 (95, 140) -7 (-25, 8)a 9 (-5, 26)b

Triglycerides (fasted) 89 (69, 114) -11 (-31, 11)a 14 (-10, 43)b

Total Cholesterol to HDL ratio 3.1 (2.5, 3.7) 0.2 (-0.1, 0.7)a 0.4 (0.0, 1.0)b

TAF = tenofovir alafenamide

TDF = tenofovir disoproxil

a. P-value was calculated for change from double blind baseline at Week 96, from Wilcoxon Signed Rank test and wasstatistically significant (p < 0.001).

b. P-value was calculated for change from double blind baseline at Week 144, from Wilcoxon Signed Rank test and wasstatistically significant (p < 0.001).

Virologically suppressed adult patients in Study 4018

The efficacy and safety of tenofovir alafenamide in virologically suppressed adults with chronichepatitis B is based on 48-week data from a randomised, double-blind, active-controlled study, Study4018 (N=243 on tenofovir alafenamide; N=245 on tenofovir disoproxil), including data from patientswho participated in the open-label phase of Study 4018 from Week 48 through Week 96 (N=235remained on tenofovir alafenamide [TAF-TAF]; N=237 switched from tenofovir disoproxil totenofovir alafenamide at Week 48 [TDF-TAF]).

In Study 4018 virologically suppressed adults with chronic hepatitis B (N=488) were enrolled who hadbeen previously maintained on 245 mg tenofovir disoproxil once daily for at least 12 months, with

HBV DNA < lower limit of quantification (LLOQ) by local laboratory assessment for at least 12weeks prior to screening and HBV DNA < 20 IU/mL at screening. Patients were stratified by HBeAgstatus (HBeAg-positive or HBeAg-negative) and age (≥ 50 or < 50 years) and randomised in a 1:1ratio to switch to 25 mg tenofovir alafenamide (N=243) or remain on 245 mg tenofovir disoproxilonce daily (N=245). Mean age was 51 years (22% were ≥ 60 years), 71% were male, 82% were Asian,14% were White, and 68% were HBeAg-negative. At baseline, median duration of prior tenofovirdisoproxil treatment was 220 and 224 weeks in the tenofovir alafenamide and tenofovir disoproxilgroups, respectively. Previous treatment with antivirals also included interferon (N=63), lamivudine(N=191), adefovir dipivoxil (N=185), entecavir (N=99), telbivudine (N=48), or other (N=23). Atbaseline, mean serum ALT was 27 U/L, median eGFR by Cockcroft-Gault was 90.5 mL/min; 16% ofpatients had a history of cirrhosis.

The primary efficacy endpoint was the proportion of patients with plasma HBV DNAlevels ≥ 20 IU/mL at Week 48 (as determined by the modified US FDA Snapshot algorithm).

Additional efficacy endpoints included the proportion of patients with HBV DNA levels < 20 IU/mL,

ALT normal and ALT normalisation, HBsAg loss and seroconversion, and HBeAg loss andseroconversion. Tenofovir alafenamide was non-inferior in the proportion of patients with HBV DNA≥ 20 IU/mL at Week 48 when compared to tenofovir disoproxil as assessed by the modified US FDA

Snapshot algorithm. Treatment outcomes (HBV DNA < 20 IU/mL by missing=failure) at Week 48between treatment groups were similar across subgroups by age, sex, race, baseline HBeAg status, and

ALT.

Treatment outcomes of Study 4018 at Week 48 and Week 96 are presented in Table 7 and Table 8.

Table 7: HBV DNA Efficacy Parameters at Week 48a,b and Week 96b,c

TAF TDF TAF-TAF TDF-TAF(N=243) (N=245) (N=243) (N=245)

Week 48 Week 96

HBV DNA ≥ 20 IU/mLb,d 1 (0.4%) 1 (0.4%) 1 (0.4%) 1 (0.4%)

Treatment Differencee 0.0% (95% CI = -1.9% to 2.0%) 0.0% (95% CI = -1.9% to 1.9%)

HBV DNA < 20 IU/mL 234 (96.3%) 236 (96.3%) 230 (94.7%) 230 (93.9%)

Treatment Differencee 0.0% (95% CI = -3.7% to 3.7%) 0.9% (95% CI = -3.5% to 5.2%)

No Virologic Data 8 (3.3%) 8 (3.3%) 12 (4.9%) 14 (5.7%)

Discontinued Study

Drug Due to AE or

Death and Last 2 (0.8%) 0 3 (1.2%) 1 (0.4%)

Available HBV DNA< 20 IU/mL

Discontinued Study

Drug Due to Other

Reasonsf and Last 6 (2.5%) 8 (3.3%) 7 (2.9%) 11 (4.5%)

Available HBV DNA< 20 IU/mL

Missing Data During

Window but on Study 0 0 2 (0.8%) 2 (0.8%)

Drug

TDF = tenofovir disoproxil

TAF = tenofovir alafenamide

a. Week 48 window was between Day 295 and 378 (inclusive).

b. As determined by the modified US FDA-defined snapshot algorithm.

c. Open-label phase, Week 96 window is between Day 589 and 840 (inclusive).

d. No patient discontinued treatment due to lack of efficacy.

e. Adjusted by baseline age groups (< 50, ≥ 50 years) and baseline HBeAg status strata.

f. Includes patients who discontinued for reasons other than an AE, death or lack of efficacy, e.g., withdrew consent, loss tofollow-up, etc.

Table 8: Additional Efficacy Parameters at Week 48 and Week 96a

TAF TDF TAF-TAF TDF-TAF(N=243) (N=245) (N=243) (N=245)

Week 48 Week 96

ALT

Normal ALT (Central Lab) 89% 85% 88% 91%

Normal ALT (AASLD) 79% 75% 81% 87%

Normalised ALT (Central

Lab)b,c,d 50% 37% 56% 79%

Normalised ALT (AASLD)e,f,g 50% 26% 56% 74%

Serology

HBeAg Loss /

Seroconversionh 8%/3% 6%/0 18%/5% 9%/3%

HBsAg Loss /

Seroconversion 0/0 2%/0 2%/1% 2%/< 1%

TDF = tenofovir disoproxil

TAF = tenofovir alafenamide

a. Missing = failure analysis

b. The population used for analysis of ALT normalisation included only patients with ALT above upper limit of normal(ULN) of the central laboratory range (> 43 U/L males 18 to < 69 years and > 35 U/L males ≥ 69 years; > 34 U/L females18 to < 69 years and > 32 U/L females ≥ 69 years) at baseline.

c. Proportion of patients at Week 48: TAF, 16/32; TDF, 7/19.

d. Proportion of patients at Week 96: TAF, 18/32; TDF, 15/19.

e. The population used for analysis of ALT normalisation included only patients with ALT above ULN of the 2018

American Association of the Study of Liver Diseases (AASLD) criteria (35 U/L males and 25 U/L females) at baseline.

f. Proportion of patients at Week 48: TAF, 26/52; TDF, 14/53.g. Proportion of patients at Week 96: TAF, 29/52; TDF, 39/53h. The population used for serology analysis included only patients with antigen (HBeAg) positive and anti-body (HBeAb)negative or missing at baseline.

Changes in bone mineral density in Study 4018

The mean percentage change in BMD from baseline to Week 48 as assessed by DXA was +1.7% withtenofovir alafenamide compared to −0.1% with tenofovir disoproxil at the lumbar spine and +0.7%compared to −0.5% at the total hip. BMD declines of greater than 3% at the lumbar spine wereexperienced by 4% of tenofovir alafenamide patients and 17% of tenofovir disoproxil patients at Week48. BMD declines of greater than 3% at the total hip were experienced by 2% of tenofovir alafenamidepatients and 12% of tenofovir disoproxil patients at Week 48.

In the open-label phase, mean percentage change in BMD from baseline to Week 96 in patients whoremained on tenofovir alafenamide was +2.3% at the lumbar spine and +1.2% at the total hip,compared to +1.7% at the lumbar spine and +0.2% at the total hip in those who switched fromtenofovir disoproxil to tenofovir alafenamide at Week 48.

Changes in renal laboratory tests in Study 4018

The median change from baseline to Week 48 in eGFR by Cockcroft-Gault method was +2.2 mL perminute in the tenofovir alafenamide group and −1.7 mL per minute in those receiving tenofovirdisoproxil. At Week 48, there was a median increase from baseline in serum creatinine among patientsrandomised to continue treatment with tenofovir disoproxil (0.01 mg/dL) compared with a mediandecrease from baseline among those who were switched to tenofovir alafenamide (−0.01 mg/dL).

In the open-label phase, the median change in eGFR from baseline to Week 96 was 1.6 mL/min inpatients who remained on tenofovir alafenamide, compared to +0.5 mL/min in patients who switchedfrom tenofovir disoproxil to tenofovir alafenamide at Week 48. The median change in serumcreatinine from baseline to Week 96 was −0.02 mg/dL in those who remained on tenofoviralafenamide, compared to −0.01 mg/dL in those who switched from tenofovir disoproxil to tenofoviralafenamide at Week 48.

Changes in lipid laboratory tests in Study 4018

Changes from double-blind baseline to Week 48 and Week 96 in total cholesterol, HDL-cholesterol,

LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio are presented in Table 9.

Table 9: Median Changes in Lipid Laboratory Tests at Week 48 and Week 96

TAF TAF TAF-TAF TDF TDF TDF-TAF(N=236) (N=226) (N=220) (N=230) (N=222) N=219)

Baseline Week 48 Week 96 Baseline Week 48 Week 96(Q1, Q3) Median Median (Q1, Q3) Median Median(mg/dL) changea (Q1, change (Q1, (mg/dL) changea (Q1, change (Q1,

Q3) (mg/dL) Q3) (mg/dL) Q3) (mg/dL) Q3) (mg/dL)

Total Cholesterol 166 (147, 19 (6, 33) 16 (3, 30) 169 (147, −4 (−16, 8) 15 (1, 28)(fasted) 189) 188)

HDL-Cholesterol 48 (41, 3 (−1, 8) 4 (−1, 10) 48 (40, −1 (−5, 2) 4 (0, 9)(fasted) 56) 57)

LDL-Cholesterol 102 16 (5, 27) 17 (6, 28) 103 (87, 1 (−8, 12) 14 (3, 27)(fasted) (87,123) 120)

Triglycerides 90 (66, 16 (−3, 44) 9 (−8, 28) 89 (68, −2 (−22, 18) 8 (−8, 38)(fasted)b 128) 126)

Total Cholesterol to 3.4 (2.9, 0.2 (−0.1, 0.0 (−0.3, 3.4 (2.9, 0.0 (−0.3, 0.0 (−0.3,

HDL ratio 4.2) 0.5) 0.3) 4.2) 0.3) 0.3)

TDF = tenofovir disoproxil

TAF = tenofovir alafenamide

a. P-value was calculated for the difference between the TAF and TDF groups at Week 48, from Wilcoxon Rank Sum testand was statistically significant (p < 0.001) for median changes (Q1, Q3) from baseline in total cholesterol,

HDL-cholesterol, LDL-cholesterol, triglycerides and total cholesterol to HDL ratio.

b. Number of patients for triglycerides (fasted) for TAF group was N=235 at baseline, N=225 at Week 48 and N=218 for

TAF-TAF group at Week 96.

Renal and/or hepatic impairment Study 4035

Study 4035 was an open-label clinical study to evaluate the efficacy and safety of switching fromanother antiviral regimen to tenofovir alafenamide in virologically suppressed HBV-infected patients.

Part A of the study included patients with moderate to severe renal impairment (eGFR by Cockcroft-

Gault method between 15 and 59 mL/min; Cohort 1, N = 78) or ESRD (eGFR by Cockcroft-Gaultmethod < 15 mL/min) on hemodialysis (Cohort 2, N = 15). Part B of the study included patients(N = 31) with moderate or severe hepatic impairment (Child-Pugh Class B or C at screening or ahistory of CPT score ≥ 7 with any CPT score ≤ 12 at screening).

The primary endpoint was the proportion of patients with HBV DNA < 20 IU/mL at Week 24.

Secondary efficacy endpoints at Weeks 24 and 96 included the proportion of patients with HBV DNA< 20 IU/mL and target detected/not detected (ie, < LLOD), the proportion of patients with biochemicalresponse (normal ALT and normalised ALT), the proportion of patients with serological response (lossof HBsAg and seroconversion to anti-HBs and loss of HBeAg and seroconversion to anti-HBe in

HBeAg-positive patients) and change from baseline in CPT and Model for End Stage Liver Disease(MELD) scores for hepatically impaired patients in Part B.

Renally impaired adult patients in Study 4035, Part A

At baseline, 98% (91/93) of patients in Part A had HBV DNA < 20 IU/mL and 66% (61/93) had anundetectable HBV DNA level. Median age was 65 years, 74% were male, 77% were Asian, 16% were

White, and 83% were HBeAg-negative. The most commonly used HBV medication oral antiviralsincluded tenofovir disoproxil (N = 58), lamivudine (N = 46), adefovir dipivoxil (N = 46), andentecavir (N = 43). At baseline, 97% and 95% of patients had ALT ≤ ULN based on central laboratorycriteria and 2018 AASLD criteria, respectively; median eGFR by Cockcroft-Gault was 43.7 mL/min(45.7 mL/min in Cohort 1 and 7.32 mL/min in Cohort 2); and 34% of patients had a history ofcirrhosis.

Treatment outcomes of Study 4035 Part A at Weeks 24 and 96 are presented in Table 10.

Table 10: Efficacy Parameters for Renally Impaired Patients at Weeks 24 and 96

Cohort 1a Cohort 2b Total(N=78) (N= 15) (N=93)

Week 24 Week 96 Week 24 Week 96 Week 24 Week 96d

HBV DNAc

HBV DNA < 20 76/78 65/78 15/15 13/15 91/93 78/93

IU/mL (97.4%) (83.3%) (100.0%) (86.7%) (97.8%) (83.9%)

ALTc

Normal ALT (Central 72/78 64/78 14/15 13/15 86/93 77/93

Lab) (92.3%) (82.1%) (93.3%) (86.7%) (92.5%) (82.8%)

Normal ALT 68/78 58/78 14/15 13/15 82/93 71/93(AASLD)e (87.2%) (74.4%) (93.3%) (86.7%) (88.2%) (76.3%)

a. Part A Cohort 1 includes patients with moderate or severe renal impairment

b. Part A Cohort 2 includes patients with ESRD on hemodialysis

c. Missing = Failure analysis

d. The denominator includes 12 patients (11 for Cohort 1 and 1 for Cohort 2) who prematurely discontinued study drug.

e. 2018 American Association of the Study of Liver Diseases (AASLD) criteria

Hepatically impaired adult patients in Study 4035, Part B

At baseline, 100% (31/31) of patients in Part B had baseline HBV DNA < 20 IU/mL and 65% (20/31)had an undetectable HBV DNA level. Median age was 57 years (19% ≥ 65 years), 68% were male,81% were Asian, 13% were White, and 90% were HBeAg-negative. The most commonly used HBVmedication oral antivirals included tenofovir disoproxil (N = 21), lamivudine (N = 14), entecavir (N =14), and adefovir dipivoxil (N = 10). At baseline, 87% and 68% of patients had ALT ≤ ULN based oncentral laboratory criteria and 2018 AASLD criteria, respectively; median eGFR by Cockcroft-Gaultwas 98.5 mL/min; 97% of patients had a history of cirrhosis, median (range) CPT score was 6 (5−10),and median (range) MELD score was 10 (6−17).

Treatment outcomes of Study 4035 Part B at Weeks 24 and 96 are presented in Table 11.

Table 11: Efficacy Parameters for Hepatically Impaired Patients at Weeks 24 and 96

Part B(N=31)

Week 24 Week 96b

HBV DNAa

HBV DNA < 20 IU/mL 31/31 (100.0%) 24/31 (77.4%)

ALTa

Normal ALT (Central Lab) 26/31 (83.9%) 22/31 (71.0%)

Normal ALT (AASLD)c 25/31 (80.6%) 18/31 (58.1%)

CPT and MELD Score

Mean change from Baseline in CPT Score (SD) 0 (1.1) 0 (1.2)

Mean change from Baseline in MELD Score (SD) -0.6 (1.94) -1.0 (1.61)

CPT = Child-Pugh Turcotte;

MELD = Model for End-Stage Liver Disease

a. Missing = Failure analysis

b. The denominator includes 6 patients who prematurely discontinued study drug

c. 2018 American Association of the Study of Liver Diseases (AASLD) criteria

Changes in lipid laboratory tests in Study 4035

Small median increases from baseline to Week 24 and Week 96 in total cholesterol, HDL-cholesterol,

LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio among patients with renal or hepaticimpairment are consistent when compared with results observed from other studies involving switch totenofovir alafenamide (see section 5.1 for Studies 108, 110 and 4018), whereas decreases frombaseline in total cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio wereobserved in patients with ESRD on haemodialysis at Week 24 and Week 96.

In Study 1092, the efficacy and safety of tenofovir alafenamide were evaluated in a randomised,double-blind, placebo-controlled clinical study of treatment-naïve and treatment-experienced

HBV-infected patients between the ages of 12 to < 18 years weighing ≥ 35 kg (Cohort 1; N=47tenofovir alafenamide, N=23 placebo), and 6 to < 12 years weighing ≥ 25 kg (Cohort 2 Group 1; N=12tenofovir alafenamide, N=6 placebo). Patients were randomised to receive tenofovir alafenamide orplacebo to match once daily. Baseline demographics and HBV disease characteristics werecomparable between the two treatment arms; 58% were male, 66% were Asian, and 25% were White;7%, 23%, 24%, and 44% had HBV genotype A, B, C, and D, respectively. Overall, 99% were HBeAgpositive. At baseline, median HBV DNA was 8.1 log10 IU/mL, mean ALT was 107 U/L, median

HBsAg was 4.5 log10 IU/mL. Previous treatment included oral antivirals (23%), including entecavir(N=10), lamivudine (N=12), and tenofovir disoproxil (N=3), and/or interferons (15%). After receivingdouble-blind treatment for 24 weeks (either tenofovir alafenamide or placebo), patients rolled overwith no interruption in treatment to open-label tenofovir alafenamide.

The primary efficacy endpoint was the proportion of patients with plasma HBV DNA < 20 IU/mL at

Week 24. Additional efficacy endpoints included change from baseline in HBV DNA and ALT, ALTnormalisation, HBeAg loss and seroconversion, and HBsAg loss and seroconversion.

Treatment outcomes of Study 1092 at Week 24 and Week 48 are presented in Table 12 and Table 13.

Table 12: Efficacy Parameters for Paediatric Patients at Week 24

TAF Placebo

Cohort 1 Cohort 2 Total Cohort 1 Cohort 2 Total(N=47) Group 1 (N=59) (N=23) Group 1 (N=29)(N=12) (N=6)

HBV DNA

HBV DNA < 20 10/47 (21%) 1/12 (8%) 11/59 (19%) 0/23 (0%) 0/6 (0%) 0/29

IU/mLa (0%)

Mean (SD) change -5.04 (1.544) -4.76 (1.466) -4.98 -0.13 0.00 (0.346) -0.10from baseline in HBV (1.520) (0.689) (0.636)

DNA (log10 IU/mL)

ALT

Median (Q1, Q3) -32.0 (-63.0, -29.0 (-81.0, -32.0 (-65.0, 1.0 -12.0 (-22.0, -2.5change from baseline in -13.0) -5.5) -7.0) (-10.0, -2.0) (-15.0,

ALT (U/L) 25.0) 22.0)

Normalised ALT 28/42 (67%) 7/10 (70%) 35/52 (67%) 1/21 (5%) 0/6 1/27(Central Lab)a,b (4%)

Normalised ALT 20/46 (44%) 5/10 (50%) 25/56 0/22 0/6 0/28(AASLD)a,c,d (45%) (0%)

Serologye

HBeAg Loss and 3/46 (7%) 1/12 (8%) 4/58 (7%) 1/23 (4%) 0/6 (0%) 1/29

Seroconversiona,f (3%)

TAF = tenofovir alafenamide

a. Missing = Failure analysis

b. The population used for analysis of ALT normalisation included only patients with ALT above ULN of the centrallaboratory range at baseline. Central laboratory ULN for ALT are as follows: 34 U/L for females aged 2 or older or malesaged 1-9 years old and 43 U/L for males aged older than 9 years.

c. The population used for analysis of ALT normalisation included only patients with ALT above ULN of the AASLDcriteria (30 U/L for males and females based on the range for paediatric participants) at baseline.

d. American Association of the Study of Liver Diseases (AASLD) criteria.

e. No patient in either group had HBsAg loss or seroconversion at Week 24.

f. The population used for serology analysis included only patients with antigen (HBeAg) positive and antibody (HBeAb)negative or missing at baseline.

Table 13: Efficacy Parameters for Paediatric Patients at Week 48

TAF Placebo roll over to TAF

Cohort 1 Cohort 2 Total Cohort 1 Cohort 2 Total(N=47) Group 1 (N=59) (N=23) Group 1 (N=29)(N=12) (N=6)

HBV DNA

HBV DNA < 20 19/47 (40%) 3/12 (25%) 22/59 (37%) 5/23 1/6 (17%) 6/29 (21%)

IU/mLa (22%)

Mean (SD) change -5.65 (1.779) -5.88 -5.70 -5.06 -4.16 (2.445) -4.88 (1.867)from baseline in (0.861) (1.626) (1.703)

HBV DNA (log10

IU/mL)

ALT

Median (Q1, Q3) -38.0 (-70.0, -30.0 (-82.0, -37.0 (-70.0, -26.0 -30.5 (-53.0, -26 (-54.0,change from -12.0) -2.5) -8.0) (-55.0, -12.0) -12.0)baseline in ALT -9.0)(U/L)

Normalised ALT 33/42 (79%) 7/10 (70%) 40/52 (77%) 13/21 4/6 (67%) 17/27 (63%)(Central Lab)a,b (62%)

Normalised ALT 25/46 (54%) 5/10 (50%) 30/56 9/22 2/6 (33%) 11/28 (39%)(AASLD)a,c,d (54%) (41%)

Serologye

HBeAg Loss and 7/46 (15%) 3/12 (25%) 10/58 (17%) 2/23 0/6 (0%) 2/29 (7%)

Seroconversiona,f (9%)

TAF = tenofovir alafenamide

a. Missing = Failure analysis

b. The population used for analysis of ALT normalisation included only patients with ALT above ULN of the centrallaboratory range at baseline. Central laboratory ULN for ALT are as follows: 34 U/L for females aged 2 or older or malesaged 1-9 years old and 43 U/L for males aged older than 9 years.

c. The population used for analysis of ALT normalisation included only patients with ALT above ULN of the AASLDcriteria (30 U/L for males and females based on the range for paediatric participants) at baseline.

d. American Association of the Study of Liver Diseases (AASLD) criteria.

e. No patient in either group had HBsAg loss or seroconversion at Week 48.

f. The population used for serology analysis included only patients with antigen (HBeAg) positive and antibody (HBeAb)negative or missing at baseline.

Changes in bone mineral density in Study 1092

Among the patients treated with tenofovir alafenamide and placebo, the mean percent increase in

BMD from baseline to Week 24 was +1.6% (N=48) and +1.9% (N=23) for lumbar spine, and +1.9%(N=50) and +2.0% (N=23) for whole body, respectively. At Week 24, mean changes from baseline

BMD Z-scores were +0.01 and -0.07 for lumbar spine, and -0.04 and -0.04 for whole body, for thetenofovir alafenamide and placebo groups, respectively.

In the open-label phase, mean percentage increase in BMD from baseline to Week 48 for lumbar spineand whole body was +3.8% (N=52) and +3.0% (N=54) in patients who remained on tenofoviralafenamide, compared to +2.8% (N=27) and +3.7% (N=27) in those who switched from placebo totenofovir alafenamide at Week 24, respectively. At Week 48, mean changes from baseline

BMD-Z scores for lumbar spine and whole body were -0.05 and -0.15 for patients who remained ontenofovir alafenamide, compared to -0.12 and -0.07 for those who switched to tenofovir alafenamide,respectively.

BMD declines of 4% or greater at lumbar spine and whole body at Week 24 and Week 48 arepresented in Table 14.

Table 14: Bone Mineral Density Decreases of 4% or Greater for Paediatric Patients at Weeks 24and 48 (Whole Body/Lumbar Spine DXA Analysis Set)

TAF Placebo roll over to TAF at Week 24

Cohort 1 Cohort 2 Total Cohort 1 Cohort 2 Total(N=44a) Group 1 (N=56) (N=21) Group 1 (N=27)(N=12) (N=6)

Week 24

Whole body at least 4% 0/39 1/11 (9.1%) 1/50 0/18 0/5 0/23decreaseb (2.0%)

Lumbar spine at least 4% 0/37 3/11 (27.3%) 3/48 0/18 0/5 0/23decreasec (6.3%)

Week 48

Whole body at least 4% 1/42 0/12 1/54 1/21 0/6 1/27decreaseb (2.4%) (1.9%) (4.8%) (3.7%)

Lumbar spine at least 4% 0/40 2/12 (16.7%) 2/52 0/21 1/6 (16.7%) 1/27decreasec (3.8%) (3.7%)

TAF = tenofovir alafenamide

Denominator is the number of patients with nonmissing postbaseline values.

a. N=42 for Lumbar Spine DXA Analysis Set in Cohort 1 TAF

b. Only patients with nonmissing whole body bone mineral density at baseline were included in the Whole Body DXA

Analysis Set.

c. Only patients with nonmissing lumbar spine bone mineral density at baseline were included in the Lumbar Spine DXA

Analysis Set.

Following oral administration of tenofovir alafenamide under fasted conditions in adult patients withchronic hepatitis B, peak plasma concentrations of tenofovir alafenamide were observedapproximately 0.48 hours post-dose. Based on Phase 3 population pharmacokinetic analysis in patientswith chronic hepatitis B, mean steady state AUC0-24 for tenofovir alafenamide (N = 698) and tenofovir(N = 856) were 0.22 µg*h/mL and 0.32 µg*h/mL, respectively. Steady state Cmax for tenofoviralafenamide and tenofovir were 0.18 and 0.02 µg/mL, respectively. Relative to fasting conditions, theadministration of a single dose of tenofovir alafenamide with a high fat meal resulted in a65% increase in tenofovir alafenamide exposure.

The binding of tenofovir alafenamide to human plasma proteins in samples collected during clinicalstudies was approximately 80%. The binding of tenofovir to human plasma proteins is less than 0.7%and is independent of concentration over the range of 0.01-25 µg/mL.

Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for> 80% of an oral dose. In vitro studies have shown that tenofovir alafenamide is metabolised totenofovir (major metabolite) by carboxylesterase-1 in hepatocytes; and by cathepsin A in peripheralblood mononuclear cells (PBMCs) and macrophages. In vivo, tenofovir alafenamide is hydrolysedwithin cells to form tenofovir (major metabolite), which is phosphorylated to the active metabolite,tenofovir diphosphate.

In vitro, tenofovir alafenamide is not metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or

CYP2D6. Tenofovir alafenamide is minimally metabolised by CYP3A4.

Renal excretion of intact tenofovir alafenamide is a minor pathway with < 1% of the dose eliminatedin urine. Tenofovir alafenamide is mainly eliminated following metabolism to tenofovir. Tenofoviralafenamide and tenofovir have a median plasma half-life of 0.51 and 32.37 hours, respectively.

Tenofovir is renally eliminated from the body by the kidneys by both glomerular filtration and activetubular secretion.

Tenofovir alafenamide exposures are dose proportional over the dose range of 8 to 125 mg.

Age, gender and ethnicity

No clinically relevant differences in pharmacokinetics according to age or ethnicity have beenidentified. Differences in pharmacokinetics according to gender were not considered to be clinicallyrelevant.

In patients with severe hepatic impairment, total plasma concentrations of tenofovir alafenamide andtenofovir are lower than those seen in patients with normal hepatic function. When corrected forprotein binding, unbound (free) plasma concentrations of tenofovir alafenamide in severe hepaticimpairment and normal hepatic function are similar.

No clinically relevant differences in tenofovir alafenamide or tenofovir pharmacokinetics wereobserved between healthy patients and patients with severe renal impairment (estimated CrCl > 15 but< 30 mL/min) in studies of tenofovir alafenamide (Table 15).

Exposures of tenofovir in patients with ESRD (estimated creatinine clearance < 15 mL/min) onchronic haemodialysis who received tenofovir alafenamide (N = 5) were substantially higher than inpatients with normal renal function (Table 15). No clinically relevant differences in tenofoviralafenamide pharmacokinetics were observed in patients with ESRD on chronic haemodialysis ascompared to those with normal renal function.

Table 15: Pharmacokinetics of Tenofovir Alafenamide and its Metabolite Tenofovir in Patientswith Renal Impairment as Compared to Patients with Normal Renal Function

AUC (mcg*hour per mL)

Mean (CV%)

Normal renal function Severe renal impairment ESRD on haemodialysis

Estimated Creatinine ≥ 90 mL per minute 15-29 mL per minute < 15 mL per minute

Clearancea (N = 13)b (N = 14)b (N = 5)c

Tenofovir alafenamide 0.27 (49.2)d 0.51 (47.3)d 0.30 (26.7)e

Tenofovir 0.34 (27.2)d 2.07 (47.1)d 18.8 (30.4)f

CV = coefficient of variation

a. By Cockcroft-Gault method.

b. PK assessed on a single dose of tenofovir alafenamide 25 mg in patients with normal renal function and in patients withsevere renal impairment in Study GS-US-120-0108.

c. PK assessed prior to haemodialysis following multiple-dose administration of tenofovir alafenamide 25 mg in 5 HBV-infected patients in Study GS-US-320-4035. These patients had a median baseline eGFR by Cockcroft-Gault of7.2 mL/min (range, pct. 4.8 to 12.0).

d. AUCinf.

e. AUClast.

f. AUCtau.

Steady-state pharmacokinetics of tenofovir alafenamide and its metabolite tenofovir were evaluated in

HBV-infected paediatric patients 12 to < 18 years weighing ≥ 35 kg and 6 to < 12 years weighing ≥ 25kg (Table 16).

Table 16: Pharmacokinetics of Tenofovir Alafenamide and its Metabolite Tenofovir in

Paediatric Patients Aged 6 to < 18 Years and Adults

Parameter 6 to < 12 years old weighing ≥ 12 to < 18 years old weighing Adultsb

Mean (CV%) 25 kga ≥ 35 kga

TAF Tenofovir TAF Tenofovir TAF Tenofovir

Cmax (µg/mL) 0.185 (77.7) 0.017 (19.7) 0.169 (80.9) 0.015 (27.4) 0.178 0.017(53.4) (35.2)

AUCtau(µg*h/mL) 0.206 (61.3) 0.298 (23.1) 0.215 (91.3) 0.251 (23.6) 0.216 0.322(66.6) (31.5)

Ctrough (µg/mL) NA 0.010 (29.5) NA 0.009 (25.6) NA 0.011(33.0)

CV = coefficient of variation; TAF= tenofovir alafenamide; NA = not applicable

a. Population PK-derived parameters from Study 1092 (6 to < 12 years old weighing ≥ 25 kg, N=12; 12 to < 18 years oldweighing ≥ 35 kg, N=47).

b. Population PK-derived parameters from Studies 108 and 110 (TAF: N=698, Tenofovir: N=856).

Non-clinical studies in rats and dogs revealed bone and kidney as the primary target organs of toxicity.

Bone toxicity was observed as reduced BMD in rats and dogs at tenofovir exposures at least four timesgreater than those expected after administration of tenofovir alafenamide. A minimal infiltration ofhistiocytes was present in the eye in dogs at tenofovir alafenamide and tenofovir exposures ofapproximately 4 and 17 times greater, respectively, than those expected after administration oftenofovir alafenamide.

Tenofovir alafenamide was not mutagenic or clastogenic in conventional genotoxic assays.

Because there is a lower tenofovir exposure in rats and mice after tenofovir alafenamideadministration compared to tenofovir disoproxil, carcinogenicity studies and a rat peri-postnatal studywere conducted only with tenofovir disoproxil. No special hazard for humans was revealed inconventional studies of carcinogenic potential with tenofovir disoproxil (as fumarate) and toxicity toreproduction and development with tenofovir disoproxil (as fumarate) or tenofovir alafenamide.

Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy orfoetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in aperi-postnatal toxicity study at maternally toxic doses. A long-term oral carcinogenicity study in miceshowed a low incidence of duodenal tumours, considered likely related to high local concentrations inthe gastrointestinal tract at the high dose of 600 mg/kg/day. The mechanism of tumour formation inmice and potential relevance for humans is uncertain.

Lactose monohydrate

Microcrystalline cellulose (E460(i))

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

Iron oxide yellow (E172)

Not applicable.

4 years.

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

High density polyethylene (HDPE) bottles, enclosed with a polypropylene continuous-thread,child-resistant cap, lined with an induction-activated aluminium foil liner. Each bottle containssilica gel desiccant and polyester coil.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets andouter cartons containing 90 (3 bottles of 30) film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/16/1154/001

EU/1/16/1154/002

Date of first authorisation: 09 January 2017

Date of latest renewal: 16 December 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.